Dr. Becker,
panel chair, began by noting that the panel was meeting to discuss and make
recommendations to the Food and Drug Administration (FDA) on the pre-market
application (PMA) P970003/S50, the Cyberonics, Inc., Vagus Nerve Stimulator
(VNS) Therapy System. This device is indicated for adjunctive long-term
treatment of chronic or recurrent depression for patients over the age of 18
who are experiencing a major depressive episode with no adequate response to
two or more antidepressant treatments. She invited panel members to introduce
themselves.

PANEL UPDATE

Theodore R.
Stevens, Chief, Restorative Devices Branch, stated that the Concentric Medical
MERCI Retriever device remains under review in the General Surgical Devices
Branch. FDA has recently published a draft guidance and a reclassification
proposed rule for the vascular and neurovascular embolization devices; the
comment period ended May 25. Several devices have been cleared that were
reviewed under the Orthopedic Devices Panel, including several PMMA cements
used for pathological fracture of the vertebral body. These 510(k)s were
cleared based on the reclassification of bone cements.

OPEN PUBLIC HEARING

Colleen
Kelly, a patient in the D-01 Cyberonics study, asked the panel to approve
VNS because it offers a viable alternative to those suffering from treatment
resistant depression (TRD). She said that she had exhausted all treatment
options for her depression, including drugs, yoga, and 33 consecutive
treatments of electric convulsive therapy (ECT). Ms. Kelly reported that she
has had the device for 4 ½ years. She still experiences brief periods of
depression and recognizes the devices shortcomings, but she feels there is no
other possible treatment for her condition.

Lydia Lewis, President,
Depression and Bipolar Support Alliance, said that she was speaking to the
panel to highlight the critical need for new therapies, not necessarily to
support the approval of VNS. She noted that more than 30,000 people take their
lives each year because they do not respond to the current treatments for
depression and bipolar disorder. Ms. Lewis showed a photograph of Barbie, her
co-worker’s sister who eventually committed suicide, and discussed Barbie’s
extensive efforts to combat depression. She asked the panel to do all they
could to help people with TRD.

Lauri I.
Sandoval, a patient in the Cyberonics study, showed a video of herself 5
years ago, before having the VNS implantation, being assessed for chronic
depression. She had just resigned her job and been diagnosed with TRD. Ms.
Sandoval decided to participate in the VNS device study; eventually, she said,
life became “wonderful.” Three months ago she felt no throat sensation from the
device and hoped the battery was dead. She underwent implantation of the “new
and improved” VNS device, which will not need batteries for 8 to 10 years.

Irvin J.
Muszynski, J.D., Director, Office of Health Care Systems and Financing at the
American Psychiatric Association, spoke about TRD from the point of view of
employers and third party payers. He went over the prevalence of diagnosable
depressive disorders, including an estimate that 20-30% of those diagnosed with
depression do not respond to treatment. From an economic point of view, Mr.
Muszynski said that the cost of treatment for those who are even “mildly
resistant” is easily double that of patients who do respond; those who are
severely resistant to treatment incur costs four times greater than those who do
respond. He added that the World Health Organization reports that depression is
the fourth leading cause of disability worldwide and may become the second or
first cause in the next decade. Mr. Muszynski told the panel that improved
early identification and long-term management techniques are needed, as well as
new treatments.

Charles
Donovan, a patient in the Cyberonics D-02 study, read the letter he
recently sent to the FDA in support of the device and urged the panel to
unconditionally approve VNS as treatment for chronic depression. In the letter
he described his history of depression and treatment. He noted that he had
undergone about 15 ECT treatments and by 1999 his condition forced him to stop
working. In 2001, he had the VNS device implanted. Mr. Donovan reported that at
first his mood only gradually improved, but now he pursues an active and
productive life. He said he is especially impressed with the sustained nature
of the treatment. Mr. Donovan noted that by the time he met with the study
investigators he had run out of treatment options. He said the side effect of
hoarseness is bothersome but tolerable.

Marna
Daventort, a patient in the Cyberonics study, explained her road to finally
getting treatment for her TRD. She noted that despite her accomplishments,
including acquiring a Ph.D., depression was something she could not master.
After trying all of the options, none of which worked for very long, Dr.
Daventort had the VNS device implanted three years ago. After about 12 to 18
months she began to see results. She said that she understands it is not a
replacement for drug therapy and other therapies, but she asked the panel to
make it an option for those patients who have no where else to turn.

Karmen
McGuffee, a patient in the Cyberonics study, showed a video of herself in
an assessment interview five years ago, before she had the VNS device
implanted. Ms. McGuffee said that she had experienced depressive symptoms since
childhood, and had been prescribed numerous drugs and other therapies and combinations.
These would work for 6 to 12 months, and then the depression would return. She
was in and out of hospitals for the depression, as well. Her family noticed an
improvement in her condition 3 to 6 weeks after VNS implantation, as if “a dark
funeral veil” had lifted. Ms. McGuffee said that she does not believe VNS has
cured her, but she knows that it has helped in ways “that words cannot
express.” She urged the panel to approve VNS for TRD.

Dr. Becker noted
that three patients and family members wrote the FDA requesting that the agency
approve the device, and one patient wrote asking that the device not be
approved. She asked if anyone in the audience wanted to speak during the open
public hearing. Mary Barrett, a patient in the D0-2 Cyberonics study, then
asked that the panel approve the VNS device. She reported that she had been
prescribed many drugs, only one of which provided her with relief but she
stopped taking it because of side effects. Ms. Barrett received the VNS implant
in 2001; she said that the parameters had to be increased but afterwards she
better for the first time since having to discontinue the medication with side
effects. She added that she volunteered for the study as a last resort.

SPONSOR PRESENTATION

Alan Totah, Vice President for Regulatory
Affairs and Quality at Cyberonics, introduced the sponsor’s presenters and
the outside experts. Mr. Totah presented the indications for use of the VNS
device and the operation of the device. He noted that there is no FDA-approved
treatment for this level of chronic or recurrent depression. The VNS system for
TRD works exactly like the VNS system for epilepsy, unanimously approved by the
FDA in 1997; more than 29,000 epilepsy patients are using the device. The
device is typically programmed on for 30 seconds and off for 5 minutes, 24
hours a day and 7 days a week. Surgical complications are minimal. The patient
can temporarily turn off the device if hoarseness is problem during singing or
public speaking.

Mr. Totah
discussed the regulatory history of the device. Studies to use the device began
in 1998 after some epilepsy patients using the VNS device reported mood
elevation. FDA granted expedited review status in July 1999; in January of 2002
the D-02 acute 12-week study was unblinded and the results were analyzed. The
primary endpoint for this study did not reach statistical significance;
however, the results did show a positive trend in favor of VNS for TRD and a
key secondary endpoint was statistically significant. In September 2002, Cyberonics
submitted a revised D-02 long-term and D-02 versus D-04 analysis to FDA. The
PMA supplement was submitted October 2003; since then, Cyberonics has responded
to FDA’s deficiency letter regarding the PMA.

Mr. Totah
explained the changes Cyberonics made when the acute study endpoint did not
reach statistical significance. They added an active control for the D0-2
outcomes to analyze long-term effectiveness and a one-year comparison of D0-2
patients treated with adjunctive VNS with D0-4 patients treated only with
standard-of-care. This provided the FDA with 12-month data on 460 patients with
TRD.

A. John Rush, M.D., Principal Investigator
for the D-02 study and Professor of Psychiatry at the University of Texas
Southwestern Medical Center explained the personal and public health impact
of TRD and treatment of TRD using the VNS device. Sixteen percent of Americans
will experience major depressive disorder (MDD) in their lifetime; it is the
second most disabling condition in the United States. Dr. Rush defined TRD as
the lack of an adequate clinical response after two well-delivered treatments
and discussed its symptoms; more than 20% of depressed patients suffer from TRD
given this definition. TRD is a chronic, disabling disease similar in scope to
chronic heart failure, except that TRD patients have a high suicide risk. ECT
is currently the best response clinicians have to TRD, but it cannot be used
long-term due to adverse effects.

Dr. Rush
reported data on relapse rates in depressive patients (non-TRD), and noted that
the rates are as high as 57% when patients are on medications; even after ECT
and drug therapy the relapse rates for TRD patients in H. A. Sackeim’s study (JAMA
2001;285:1299-1307) reached as high as 60%. Dr. Rush added that these are
the most difficult to treat patients he has ever included in a trial—they would
never have been accepted into any pharmaceutical trial. These are extremely
resistant patients “at the end of the line.” There is currently no FDA-approved
treatment for TRD.

Richard L.
Rudolph, M.D., Vice President for Clinical and Medical Affairs and Chief Medical
Officer at Cyberonics, began his overview of the clinical safety and
effectiveness data from the VNS studies by discussing the sponsor’s rationale
for investigating the use of VNS therapy in TRD patients. These include the
mood stabilizing effects of anticonvulsants, neuroimaging data, studies
confirming the anecdotal reports of mood enhancement in VNS epilepsy patients,
effects of VNS on neurotransmitters, and work on an animal antidepressant
model.

He presented
information on four of the seven VNS studies: D-01, an open label feasibility
study; D-02 acute, a double-blind, randomized, sham treatment-controlled study;
D-02 long-term, an open label study; and D-04, a prospective, observational
study of TRD patients treated with standard-of-care therapies for comparison
with D-02. The other three studies did not apply to the treatment indications
under review or are ongoing. He noted that the comparison of the 12-month
outcomes for the D-02 patients receiving adjunctive VNS therapy with the D-04
patients receiving standard-of-care therapy provide the strongest evidence for
the effectiveness of the adjunctive VNS therapy.

Dr. Rudolph
noted that the main inclusion criteria were identical for both the D-02 and
D-04 studies, and the patient populations in both were comparable. He explained
the reasons why the non-randomized D-04 study was an appropriate control for
the D-02 long-term study, including that is was a prospectively designed study
for comparison with D-02; it represents a clinical relevant active treatment
control corresponding the indication for VNS; there were overlapping
investigation sites during a similar time period; and the D-04 study includes a
large sample size which facilitates statistical comparisons. Dr. Rudolph also
explained that outcomes in depression studies are measured using standardized
and validated rating scales; in multidimensional scales, such as the Inventory
of Depressive Symptomatology—Self Report (ISD-SR) and the Hamilton Rating Scale
for Depression (HRSD); the higher the total score the more severely depressed
is the patient. The main baseline scores for patients in their studies fall in
the severe range.

Dr. Rudolph
compared the outcomes of the D-02 and D-04 studies, noting that there was a
high level of statistical significance on the primary outcome analysis over 12
months: specifically, the D-04 patients improved very little in their IDS-SR
scores while the D-02 patients receiving adjunctive VNS improved to a greater
degree in absolute measurement and their IDS-SR scores were lower, as well. The
statistical significance is maintained when alternative analysis methodologies
are used. The results of the primary analysis were also confirmed when looking
at a variety of secondary analyses over 12 months. The response criteria rate
using the IDS-SR scale for patients in the D-02 group was 22% versus 12% for
the D-04 group; the response criteria rate using the HRSD scale for patients in
the D-02 group was 30% versus 13% for the D-04 group.

Dr. Rudolph also
went over how the investigators made sure that the VNS treatment was
responsible for the differences between the D-02 and D-04 groups, and not such
factors as baseline patient differences, medications, ECT, and placebo effect.
Of the 56 patients who, at 3 months, fell into the extraordinary, highly
meaningful, or meaningful clinical benefit categories, 71% maintained at least
a meaningful clinical benefit through 12 months with adjunctive VNS therapy. Of
the 118 patients who, at 3 months, did not fall into the extraordinary, highly
meaningful, or meaningful clinical benefit categories, 47% first obtained
meaningful to extraordinary benefit after more than 3 months of adjunctive VNS
therapy. Dr. Rudolph said that this was “the most persuasive data as to VNS’s
long-term effectiveness.”

Dr. Rudolph’s
discussed the epilepsy safety results as compared with the depression safety
results. The depression studies safety overview showed that the adverse events
were primarily stimulation-related and minor. Voice alteration (hoarseness) was
the most common adverse event, affecting 68% of patients. The suicide attempts
and suicide rates for study participants were comparable with the published
literature looking at active treatment groups and placebo groups.

Dr. Rush offered
closing remarks to the sponsor’s presentation by looking at the data and
information presented from the point of view of a clinician. He reminded panel
members that more than half of the individuals being treated had received ECT
resulting in no sustained benefit. Dr. Rush explained how the study recruited
patients. They went to those physicians who did complex medication management
for depressed patients and asked for two each of their “very worst, most
difficult depressed patients.” He said the clinical results of the study are
meaningful because 1) the benefit for many in this otherwise untreatable
population gets better with time; 2) placebos typically work early in treatment
and their results eventually wear off, but this device seems to have the
opposite effect; 3) while the induction of hypomania is an adverse event, it
was more common in bipolar disorder patients; and 4) patients have seen
improvement in results after battery replacement, which shows a significant
effect. He finished the presentation by noting that, given the statistics on
suicide and TRD, four individuals have committed suicide over the previous 2 ½
hours, and if VNS can help one out five of TRD patients it should be approved.

FDA PRESENTATION

Carlos
L. Peña, Ph.D., FDA lead reviewer, described for the panel the indications
for VNS and the components of the device. He presented the regulatory history,
noting that the FDA approved the device in 1997 for epilepsy.In 1998 the sponsor embarked on a pilot
study for TRD indications (D-01).The pilot
D-01 study results led to the pivotal D-02 study in 2000; however, unblinding
the pivotal D-02 study in January 2002, data failed to demonstrate a difference
in improvement between those with active stimulation and sham stimulation for the
primary efficacy endpoint. The sponsor suggested that the full effect of VNS might
take longer, and proposed the non-significant risk control study called D-04 as
a comparison to the pivotal D-02 long-term clinical data. The FDA advised the
sponsor of serious concerns about the validity of this comparison, due to a
lack of a randomized data set. The sponsor submitted their PMA in October 2003.

Dr.
Peña reviewed the pilot D-01 study, the pivotal D-02 study, and the
observational control D-04 study. He noted that the pilot D-01 primary efficacy
endpoint was the proportion of patients that responded to therapy (50% or more
decrease in their HRSD] score after 12 weeks). Twenty-one of 59 patients
implanted underwent concomitant changes in their treatment, and total of 77
serious adverse effects appeared in 38 patients. At the acute phase exit, 18 of
59 patients were defined as responders.

In
the pivotal D-02 study, patients were required to maintain stable medication
regimen during the acute phase but were allowed concomitant medications and ECT
treatment during the long-term phase. During the pivotal D-02 acute phase, 9
patients had changes in their concomitant treatment (no ECT treatment reported)
while 169 of the 205 evaluable patients in the long-term phase had changes in
their concomitant treatment; 14 patients also received ECT during the long-term
phase. The primary efficacy endpoint of the acute randomized, controlled phase failed
to show a significant difference between the treatment and sham control groups
(15% versus 10%).

In
the control D-04 study, Dr. Peña noted that it was conducted under local IRB
jurisdiction and expressed concern over the D0-2/D-04 enrollment outcomes and
time of overlap, noting that the majority of control D-04 subjects enrolled
after the pivotal D-02 study closed. According to the sponsor, he added, sites
were more focused on the pivotal D-02 treatment study rather than the
observational, control D-04 study. After the pivotal D-02 study closed,
subjects that had expressed an interest in the pivotal D-02 study were subjects
that typically enrolled in the control D-04 study. The demographic
characteristics between the two study participants were for the most part
comparable; however, there were significant differences in ECT history between
the two study populations. He also expressed concern about the “permissive use
of concomitant treatments during the long-term study” and how that might impact
the determination of effectiveness of the VNS device

Michael
Schlosser, M.D., FDA clinical reviewer, began by reviewing the stimulation
parameters used in the study. The study protocol limited current output to
0.25–3.5 mA, with adjustments in 0.25 mA steps until a maximum tolerable level
was reached. The programming phase of the study’s acute phase lasted two weeks,
during which programmers could adjust a participant’s current level. The
sponsor sent a letter to the pivotal D-02 study investigators in April 2002
outlining a new stimulation protocol used for nonresponders.

Dr.
Schlosser first covered the safety data for the pilot D-01 study, in which
every subject reported at least one adverse event. Greater than 50% of the
patients reported serious adverse events, including 12 suicide attempts, 34
cases of worsening depression, and one death during a surgery for rectal
prolapse.

In
the pivotal D-02 acute phase, nearly every patient reported an adverse event;
severe adverse events were reported among 61 subjects in the treatment control
group (including one suicide) and 73 in the sham group. In the long-term phase
of the pivotal D-02 study, there were seven suicide attempts. Dr. Schlosser
remarked that the sponsor believes that the 62 episodes of depression among 31
subjects in the long-term phase to be due to a lack of efficacy of the device
than a true serious adverse effect. Safety data was not collected for the
observational, control D-04 study.

The
European D-03 study, an open label, non-randomized, single-arm study, is still underway.
The 47 subjects receiving implantation of the VNS device reported 14 serious
adverse events, including two suicides. Dr. Schlosser also briefly presented
the Sponsor-Investigator D-06 study, an open label, non-randomized, study with
a single treatment arm that looked at VNS therapy for patients with rapid
cycling bipolar disorder. One suicide and two suicide attempts were reported in
the seven implanted patients.

Dr. Schlosser
noted that the FDA is concerned about the number of suicide attempts among the
participants in these studies. He reminded panel members that the safety
analysis of a device is done as a risk-benefit equation; therefore, the safety
in the epilepsy population does not equate safety in the TRD population.

Dr.Peña then summarizedthe efficacy and safety issues.He noted that the absence of systematically
collected safety data in the observational control D-04 study to compare with
the investigational study is a concern when determining the safety of the VNS
device. FDA also had the following efficacy concerns: that the long-term
pivotal D-02 study/control D-04 study comparative analysis was not from a
randomized data set but rather from a comparison of outcomes from an
investigational device study and observational control study; that a persistent
placebo effect for patients with the VNS device was observed in the acute phase
and that patient expectation may have been greater in the pivotal D-02 study
than the observational, control D-04 study; and that permissive use of concomitant
treatments during study including the fact that concomitant medications and ECT
use were not standardized in eitherthe
D-02 long-term study or the D-04 observational study.

Chang S. Lao,
Ph.D., Division of Biostatistics, presented a comparison between the D-02
and D-04 statistical data. He evaluated the primary and secondary effectiveness
endpoints; the study sites; propensity score analysis; repeated measures linear
regression; concordance analysis (IDS-SR versus HRSD scores); and provided
statistical conclusions about the comparison between the two studies. He noted
that the 3-month double blind study reported significant values using the
IDS-SR. In the 12-month non-randomized
unblinded study comparing the pivotal D-02 study and the observational, control
D-04 study, the sponsor successfully used propensity scores to adjust for an
imbalance in measured covariates; however, the propensity scores cannot balance
unmeasured covariates.Dr. Lao noted
that the sponsor carried forward data about treatment alteration, but the
effect of this on the study’s analysis is unclear. The results of the
concordance study are unclear, as well, and there is some doubt as to whether
IDS-SR scores can be used to predict scores on the HRSD assessment.

Dr. Peña
closed by directing the panel’s attention to the five discussion
questions that ask about issues of valid scientific evidence to assure that the
device is safe and efficacious.

PANEL DISCUSSION

Dr. Becker asked
the panel if they had any questions for the FDA presenters. Dr. Ellenberg asked
Dr. Lao about the information he presented on the difference between the
pivotal D-02 study and the observational, control D-04 study at one year,
looking at improvement in IDS-SR scores and site difference issues. Dr. Lao said
that he believed that using only the overlapping sites would be a more accurate
way to complete the analysis, rather than using all 22 sites. He also discussed
why it was important to look at the sites by treatment, as there may be an
interaction between the treatment and the individual site. Dr. Wang asked about
the IDS-SR as a more relevant measure of depression. Dr. Peña responded, saying
that the FDA has concerns about lack of improvement between the treatment and
control groups using other psychometric assessment tools used by the sponsor,
which raises questions about the strength of IDS-SR outcomes.

Dr.
Becker opened the floor for panel members to ask questions of the sponsor. She
began by asking why the sponsor chose 12 weeks for the acute study and why they
didn’t extend the trial. Dr. Rudolph said that 12 weeks is standard for a drug
trial, and that by the time they unblinded the acute phase results the patients
were beyond the acute phase and it could not be continued as a double-blind
randomized trial. Dr. Ellenberg asked why the sponsor does not see the need to
do a new randomized study, given the issues around bias, enrollment timing, and
study group comparisons. Dr. Rudolph responded that every other study plan we
envisioned had significant limitations; Dr. Rush walked the panel through a
number of the other study possibilities the sponsor considered, noting that
because long-term safety of the device is now better understood, they could
conduct a randomized trial, but interactions with medication changes will still
be an issue. He added that he feels very confident about the results, given
that the 12-month outcomes are largely sustained and the number of patients
benefiting from VNS has increased. Dr. Sackeim addressed Dr. Ellenberg’s question
about the impact of patient expectations on outcomes. He said that a previous
study of ECT patients—a comparable population— found no association between
patient expectations and outcomes. He also addressed Dr. Ellenberg’s question
about bias introduced at various study sites, noting that the tapes were also
rated by third parties who had no information about where the patient was in
the treatment course.

PANEL DELIBERATIONS

Dr. Ellenberg
was scheduled to make a formal statement but declined because he agrees fully
with the FDA statistical and clinical reviews. Dr. Wang opened the panel’s
deliberations with a statement. He gave an overview of the VNS device, its
indications, components, and the sponsor’s results. The D-02 study did not meet
its efficacy endpoints, and Dr. Wang noted that the sponsor suspected that the
device’s full effect could require more than 10 weeks. This result prompted the
D-02/D-04 12-month comparison study. He noted the propensity score analysis
done on the primary endpoint analysis to reduce potential bias; Dr. Wang added
that there are still confounding possibilities due to “poorly measured” and
unmeasured variables. He continued to describe other concerns about the study
design and possible compromised efficacy results raised during the FDA’s
presentation. He noted that there were issues that made it difficult to assess
safety results in the studies, primarily because safety data were not
systematically collected in the D-04 study, providing no comparison group for
the D-02 long-term study. Dr. Wang expressed concerns about training for the
VNS device, specifically about who should implant the device; who should
program the device; how will they be trained; and what guidance is available on
titrating the current? He closed by raising questions about the implications of
device approval, such as whether there would be pressure to forgo effective but
stigmatized treatments such as ECT.

GENERAL PANEL DISCUSION

Dr. Becker
called on the panel members to offer any comments or raise any questions about
the device to both the FDA and the sponsor. Dr. Jayam-Trouth asked the sponsors
why there was a drop off in the number of responders after two years. The
sponsor said that there were four or five individuals who were explanted for
lack of efficacy, and as many as 10 patients who could not or did not return in
the time period, some because they were feeling well. About 90% still had the
device implanted at two years. Dr. Jayam-Trouth, Dr. Becker, and the sponsors
also discussed the protocols for adjusting the levels of stimulation for
participants in the treatment arm and the sham arm.

Dr. Fochtmann
asked the sponsors about the difference in the stimulus parameter settings
between the responders and the nonresponders; the sponsor answered that the
parameters were the same for nonresponders and responders in both the acute and
the long-term studies. She also asked whether there was comparable efficacy in
patients with a chronic episode lasting more than two years versus those with
multiple recurring episodes. The sponsor said that the two groups showed
comparable rates of response, but a statistical test was not done, only an
exploratory analysis. She and the sponsors also discussed the concomitant use
of antipsychotic medications.

Dr. Wang brought
up the concerns the FDA expressed about residual confounding in the D-02/D-04
propensity score adjustments and the fact that the comparative study was not
randomized. The sponsor said that they proceeded this way because of the sample
sizes were large, the measured covariates were equally distributed, and they
felt they could assume that unmeasured covariates would be equally distributed,
as well. The sponsor addressed a possible panel misunderstanding that there was
no covariate adjustment in the secondary analysis when, in fact, there was
covariate adjustment.

Dr. Jensen asked
a number of questions about safety, including why the infection rates for the
depression study patients appears to be higher than for the epilepsy patients.
The sponsor noted that only one patient required explanation due to infection
and the rest were treated with antibiotics; in fact, the infection rate for the
depression subjects was lower. Dr. Jensen also asked about Cyberonics’ position
about what is to be done with the implant in nonresponsive patients; this is of
special concern because most of the patients are relatively young and will
likely undergo a brain MRI in their lives. The sponsor noted that if the device
is left in, the patient retains risks when receiving whole-body and cervical
spine diagnostic MRIs and diathermy, but they can still undergo a head MRI. The
sponsor also said that they had not seen any long-term problems relating to
corrosion of the device’s components in the epilepsy patients. Dr. Jensen
requested more information on which clinicians are allowed to perform the
implantation and how they will be trained. The sponsor noted that they offer
proctoring and suggested that surgeons should be experienced working within the
carotid sheath, adding that about 64% of surgeons performing the procedure are
neurosurgeons. Dr. Jensen said that she supported the creation of a TRD
registry.

Dr. Ortiz
questioned the sponsor about the patient comorbidity in the study. The sponsor
noted that there were some specific exclusions in the D-02 protocol, including
patients with psychotic depression, substance abuse, schizoaffective disorder,
and mixed or rapid cycling bipolar disorders. They did not diagnose or exclude
personality disorders.

Dr. Malone made
general comments about the design of the studies. He said that the same
criteria for drug trials should be used to judge the VNS depression study data,
and that the study should have been done as a double-blind randomized study, as
appears in much of the literature on psychiatric treatment. The sponsor noted
that the literature generally refers to common depression, not necessarily TRD.
The sponsor agreed that randomized control trials should be done, but only when
they can be accomplished in a safe and ethical manner, and when the outcome of
the disorder is not “uniformly terminal.” Now that they have established
long-term safety of VNS, the sponsor believes that they could do such a study.

Ms. Wells asked
whether the sponsor had any intermediate effectiveness outcomes for the ongoing
D-03 study. The sponsor said that the response rates are similar to the D-01
study. Mr. Balo asked Dr. Lao whether the information provided earlier in the
panel discussion about the propensity score analysis and the covariate analysis
answered his concerns. Dr. Lao said that he still had some questions. Mr. Balo
asked Dr. Peña why there was never any discussion about safety data in the D0-4
study. Dr. Peña responded that the D-04 study was conducted under local IRB
jurisdiction so it required no FDA approval. He also noted to the panel that
FDA had expressed serious concerns on several occasions about the D02/D-04
comparison.

Dr. Fochtmann
had additional safety questions for the sponsor. She wondered if patients
should be screened for sleep apnea and should receive ongoing assessments for
this disorder. The sponsor said that the label already includes a warning for
obstructive sleep apnea, but there is no screening. Dr. Fochtmann expressed
concern that nonadherent patients would not carry the magnet component of the
VNS device, for cases in which they needed to turn off the stimulation. The
sponsor noted that the magnet is mostly a convenience to stop minor side
effects temporarily; they supply patients with multiple magnets for
convenience.

FDA QUESTIONS

1.A chief limitation of the
long-term D02, D04 comparative analysis is that the data are not derived from a
randomized subject data set, but rather a comparison of outcomes from an
investigational device study and observational control study.A propensity adjustment strategy was used to
reduce potential bias (i.e., patient characteristics, disease characteristics)
in the comparative analysis. This type of strategy is not able to address the
problems of potential bias due to other unmeasured patient variables (e.g.,
past thyroid dysfunction, neurotic pre-morbid personality, familial
predisposition for affective disorder, multiple loss events, or socio-cultural
level).Please discuss the impact of a
comparative analysis of non-randomized subject data, comparison of outcomes
from an investigational study and observational study, and unmeasured patient
variables upon efficacy outcomes in the PMA.

Though most panel members thought that the sponsor did a good overall job
with the comparison study data, they also noted that there were limitations in
the comparison. Panel members noted this was a unique population that
desperately needs alternative treatments and generally agreed that the device
appeared to show some promise for TRD.

2.The sponsor believes D-02 long-term outcomes are not due to a placebo
effect.Data provided in the PMA
includes a 20% (21/106) placebo effect rate in sham-treatment control subjects
at acute phase exit (12 weeks) as defined by a HAM-D score less than 18.Patient expectation of participating in an
investigational study for a new therapy (D-02 study) may have also been greater
than the expectation of participating in an observational control study.Please discuss the placebo effect and impact
upon clinical outcomes presented in the PMA.

The panel noted that the non randomized study design made it difficult to
understand or measure the placebo effect, but there was general consensus that
there was evidence of a placebo effect on the clinical outcomes. Panel members
expressed concern that the value of the blinding in the short-term study was
limited. They also suggested that only a true randomized control trial would
answer questions about placebo effect.

3.Concomitant medications and ECT use were not standardized in either the
D-02 long-term study or the D-04 observational control study.Please discuss the impact of concomitant
medications and ECT use on interpretation of the efficacy of VNS therapy for
treatment resistant depression.

The panel believed that because the study was not randomized and the
concomitant medications were not standardized, the effect of the concomitant
medications and ECT treatments on the efficacy outcomes of the VNS device was
difficult to appreciate. Some panel members suggested that more information
about the types of ECT used, as well as the specific types of concomitant
medications, would also be helpful.

4.21 CFR 860.7(d)(1) states that there is a reasonable assurance that the
device is safe when it can be determined that the probable benefits to health
from use of the device for its intended uses, when accompanied by adequate
instructions for use and warnings against unsafe use, outweigh any probable
risks.Do the clinical data in
P970003/S050 provide reasonable assurance that the device is safe?

Panel members agreed that the device appears generally safe but, based on
efficacy questions, the safety-benefit ratio cannot be determined. Panel
members recognized the limited treatment alternatives this patient population
faces, as well as the large numbers of nonresponder patients with the implanted
device and the impact this may have on their lives.

5.21 CFR 860.7(e)(1) states that there is a reasonable assurance that a
device is effective when it can be determined, based on valid scientific
evidence, that in a significant portion of the target population, the use of
the device for its intended uses and conditions of use, when accompanied by
adequate directions for use and warnings against unsafe use, will produce
clinically significant results.Considering
your responses to questions 1, 2, and 3, do the clinical data in P970003/S050
provide reasonable assurance that the device is effective?

The chairperson noted less consensus on this question than on the
previous four questions. Some panel members believed that the device is
effective; others want more rigorous testing; while others recognize the
benefit in the TRD populations despite limitations from the study design.

OPEN PUBLIC HEARING

No comments were made.

FDA AND SPONSOR SUMMATIONS

The FDA did not
offer a summation.

Cyberonics
representatives noted that the panel agreed that the device is safe. They
stressed that the study population is one in which the chance of a placebo
response is quite small. The VNS device separates itself from other TRD
treatments in the long-term benefits it provides to a population among whom
remission rates are quite high. The sponsors added that they are realizing the
possibility that 70% of patients will retain benefits from VNS treatment for 2
years. They reiterated that most of these patients have undergone 20 to 40
years of treatment; as a result, standard-of-care treatment can often be
dangerous and unacceptable.

The
sponsor suggested that, even though the D-04 was not randomized, the study
should be thought of as more than just a “haphazard control study”. It had
elements that offer a high degree of comparability and confidence to determine
efficacy. It was prospective with overlapping sites and maintained the same
principal enrollment criteria and was conducted over the same time frame as the
D-02 study. They asserted that even randomized control trails do not guarantee
equally distributed baseline covariates. The sponsor asked the panel to
consider whether the lack of a randomized study is enough to delay approval of
the device.

The
sponsor also believed that they needed to explain the full context of the
regulation mentioned in the fifth discussion question. They noted that 55% of
all approved medical device PMAs were supported by non randomized clinical
trails and 7% included no controls. The sponsor reminded the panel that TRD is
a “highly lethal” condition and in the time it takes to conduct a randomized
trial they will loose 1,000 potential patients a month to suicide. They asked
that the panel look at the patho pneumonic evidence of efficacy for the device,
as well as the trial evidence of safety, and approve the device.

VOTE

Executive
Secretary Scudiero read the panel voting options. The panel voted five to two
that the PMA P970003/S50 for the Cyberonics VNS system was approvable with the
following conditions:

1.Patients should have failed four or more trials of traditional
treatment modalities for TRD (medications and ECT) before using the VNS device.

2.Surgeons should undergo appropriate training and be
experienced working within the carotid sheath before implanting the VNS device.

3.Primary care providers should receive training on how to
electronically program the device.

4.Additional patient labeling should include information about
device complications and removal of the device, and patients should receive an
identification card.

5.The sponsor should help establish a patient registry to
collect clinical data to identify adverse effects, stimulation levels, and
information about prognostic factors.

The physician labeling should be revised as per the
following: that the study was a 12-month open label follow-up trial; in
the section on the variable effect of treatment, change the wording from
“highly statistically significant effect” to “significant effect” and
delete the P value; in point 6, change “VNS therapy should be considered”
to “VNS therapy may be considered”; in point 12, delete blood flow imaging
claims; and in point 6, delete “intolerant”.

POLL

When asked to
explain the rationale behind their votes, those panel members voting against
conditional approval believed that the data failed to show a sufficient level
of efficacy, and that a new randomized study was necessary to establish a
reasonable assurance of safety and efficacy. Those voting to approve the PMA
with conditions noted that the device demonstrated safety, and that some level
of efficacy was shown, albeit with less-than-ideal data, for a particularly
difficult group of patients to treat.

ADJOURNMENT

Dr. Becker
adjourned the meeting at 5:42 p.m.

I certify that I attended this
meeting of the Neurological Devices Advisory Panel Meeting on June 15, 2004,
and that these minutes accurately reflect what transpired.